Despite the availability of a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressant (e.g., selective serotonin reuptake inhibitors SSRIs) treatment, despite adequate dosage, duration, and compliance. Furthermore, these medications may take weeks to months to achieve their full effects, and in the meantime patients continue to suffer from their symptoms and continue to be at risk of self-harm as well as harm to their personal and professional lives. Thus, there is a clear need to develop novel and improved therapeutics for treatment-resistant major depression that are more effective and have a rapid onset of action. Preclinical and clinical studies suggest that antidepressants with a combined mechanism of action (e.g., combination of a selective serotonin-reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor) may be more effective than either agent alone in achieving remission (Nelson et al 2004). Thus, it stands to reason that other combinations of antidepressants with other mechanisms of action when combined may have a synergistic effect that is superior to an antidepressant with a single mechanism of action. Preclinical and clinical studies suggest that the dopaminergic system may play a major role in the pathophysiology of depression. Preclinical studies suggest synergistic antidepressant effects with the combination of a SSRI and a selective D3 receptor agonist in animal models of depression. Similarly, preliminary clinical studies suggest synergism with combination treatment that affects the serotonin and dopamine systems. Together, these data suggest that treatments which affect the serotonin and dopamine systems will be more effective than agents which use a single mechanism. We propose to compare the combination of a selective dopaminergic agonist and a SSRI in patients with treatment-resistant major depression. To our knowledge, this will be the only controlled double-blind study to date that will examine the efficacy of a serotonin and dopamine combination given from the start of treatment.[unreadable] Patients, ages 18 years or older, with a diagnosis of major depression (without psychotic features), will be randomized to the combination of a selective dopaminergic receptor agonist and a SSRI or either drug alone for a period of 6 weeks. Acute efficacy will be determined by demonstrating a greater remission rate using specified criteria. Approximately 85 patients with acute major depression will be enrolled in the study.[unreadable] [unreadable] Other aims of this study are to examine correlates of antidepressant response to clinical (e.g., family history), and imaging (magnetic resonance imaging/spectroscopy) correlates.